Pathophysiology Underlying Demographic and Obesity Determinants of Sleep Apnea Severity

Rationale: Sleep apnea is the manifestation of key endotypic traits, including greater pharyngeal collapsibility, reduced dilator muscle compensation, and elevated chemoreflex loop gain. Objectives: We investigated how endotypic traits vary with obesity, age, sex, and race/ethnicity to influence sleep apnea disease severity (apnea-hypopnea index [AHI]). Methods: Endotypic traits were estimated from polysomnography in a diverse community-based cohort study (Multi-Ethnic Study of Atherosclerosis, N= 1,971; age range, 54-93 yr). Regression models assessed associations between each exposure (continuous variables per 2 standard deviations [SDs]) and endotypic traits (per SD) or AHI (events/h), independent of other exposures. Generalizability was assessed in two independent cohorts. Results: Greater AHI was associated with obesity (119 events/h per 11 kg/m(2) [2 SD]), male sex (113 events/h vs. female), older age (17 events/h per 20 yr), and Chinese ancestry (15 events/h vs. White, obesity adjusted). Obesity-related increase in AHI was best explained by elevated collapsibility (10.40 SD) and greater loop gain (10.38 SD; percentage mediated, 26% [95% confidence interval (CI), 20-32%]). Male-related increase in AHI was explained by elevated collapsibility (10.86 SD) and reduced compensation (20.40 SD; percentage mediated, 57% [95% CI, 50-66%]). Age-related AHI increase was explained by elevated collapsibility (10.37 SD) and greater loop gain (10.15 SD; percentage mediated, 48% [95% CI, 34-63%]). Increased AHI with Chinese ancestry was explained by collapsibility (10.57 SD; percentage mediated, 87% [95% CI, 57-100]). Black race was associated with reduced collapsibility (20.30 SD) and elevated loop gain (10.29 SD). Similar patterns were observed in the other cohorts. Conclusions: Different subgroups exhibit different underlying pathophysiological pathways to sleep apnea, highlighting the variability in mechanisms that could be targeted for intervention.